T h e n e w e ng l a n d j o u r na l o f m e dic i n e

Original Article

Smoking Cessation, Weight Change, Type 2
Diabetes, and Mortality
Yang Hu, S.M., Geng Zong, Ph.D., Gang Liu, Ph.D., Molin Wang, Ph.D.,
Bernard Rosner, Ph.D., An Pan, Ph.D., Walter C. Willett, M.D., Dr.P.H.,
JoAnn E. Manson, M.D., Dr.P.H., Frank B. Hu, M.D., Ph.D.,
and Qi Sun, M.D., Sc.D.​​

A BS T R AC TBACKGROUND

Whether weight gain after smoking cessation attenuates the health benefits ofquitting is unclear.
METHODSIn three cohort studies involving men and women in the United States, we identified those who had reported quitting smoking and we prospectively assessedchanges in smoking status and body weight. We estimated risks of type 2 diabetes,
death from cardiovascular disease, and death from any cause among those who hadreported quitting smoking, according to weight changes after smoking cessation.
RESULTSThe risk of type 2 diabetes was higher among recent quitters (2 to 6 years sincesmoking cessation) than among current smokers (hazard ratio, 1.22; 95% confidence interval [CI], 1.12 to 1.32). The risk peaked 5 to 7 years after quitting andthen gradually decreased. The temporary increase in the risk of type 2 diabetes
was directly proportional to weight gain, and the risk was not increased among
quitters without weight gain (P<0.001 for interaction). In contrast, quitters did nothave a temporary increase in mortality, regardless of weight change after quitting.
As compared with current smokers, the hazard ratios for death from cardiovascular disease were 0.69 (95% CI, 0.54 to 0.88) among recent quitters without weight
gain, 0.47 (95% CI, 0.35 to 0.63) among those with weight gain of 0.1 to 5.0 kg,
0.25 (95% CI, 0.15 to 0.42) among those with weight gain of 5.1 to 10.0 kg, 0.33
(95% CI, 0.18 to 0.60) among those with weight gain of more than 10.0 kg, and0.50 (95% CI, 0.46 to 0.55) among longer-term quitters (>6 years since smoking
cessation). Similar associations were observed for death from any cause.
CONCLUSIONS

Smoking cessation that was accompanied by substantial weight gain was associated with an increased short-term risk of type 2 diabetes but did not mitigate thebenefits of quitting smoking on reducing cardiovascular and all-cause mortality.
(Funded by the National Institutes of Health.)n engl j med 379;7

nejm.org

From the Departments of Nutrition (Y.H.,
G.Z., G.L., W.C.W., F.B.H., Q.S.), Epidemiology (Y.H., M.W., W.C.W., J.E.M.,
F.B.H.), and Biostatistics (M.W., B.R.),
Harvard T.H. Chan School of Public
Health, and the Channing Division of
Network Medicine (M.W., W.C.W., J.E.M.,
F.B.H., Q.S.) and the Division of Preventive Medicine (J.E.M.), Department ofMedicine, Brigham and Women’s Hospital and Harvard Medical School — all in
Boston; and the Key Laboratory of Nutrition, Metabolism, and Food Safety, Institute of Nutrition and Health, Shanghai
Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai(G.Z.), and the Department of Epidemiology and Biostatistics, Ministry of Education Key Laboratory of Environment and
Health and State Key Laboratory of Environmental Health (Incubating), School of
Public Health, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan (A.P.) — both in China.
Address reprint requests to Dr. Sun at the
Department of Nutrition, Harvard T.H.
Chan School of Public Health, 665 Huntington Ave., Boston, MA 02115, or at q
­ isun@​­hsph​.­harvard​.­edu.
Drs. Y. Hu and Zong contributed equallyto this article.
N Engl J Med 2018;379:623-32.
DOI: 10.1056/NEJMoa1803626
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623

T h e n e w e ng l a n d j o u r na l o f m e dic i n e

Smoking cessation reduces the riskof major chronic diseases and extends life
expectancy,1 but considerable weight gain
may occur in quitters after cessation.2 Such weightgain is probably due to increased appetite andreduced energy expenditure3 and may discourage
quitting attempts and potentially attenuate thehealth benefits of smoking cessation throughincreasing the risk of cardiometabolic disease
and premature death.4 Despite this concern, evidence regarding the health consequences of weightgain after smoking cessation is equivocal.5-9 The
inconsistent findings may be due to the fact that
previous observational studies largely relied on
the “point prevalence”10 of smoking cessation (i.e.,
assessment of smoking status at one particularfollow-up period only), and possible changes insmoking behavior during follow-up were usually
unknown. It has been reported that more than
30% of quitters who were abstinent for 1 year
eventually had a relapse within the next decade.11
With longitudinal, repeated assessments ofsmoking status and body weight in large cohort
studies of men and women in the United States,
the current investigation aimed to evaluate therisk trajectories of disease and death among
those who reported quitting smoking, according
to body-weight changes after smoking cessation.

Me thods
Study Population and Study Oversight

We used data collected from three cohorts — theNurses’ Health Study (NHS), the Nurses’ HealthStudy II (NHS II), and the Health Professionals
Follow-up Study (HPFS) (Text 1 in the Supplementary Appendix, available with the full text of
this article at NEJM.org) — with follow-up bymeans of questionnaires eliciting medical andlifestyle information that were mailed to participants every 2 years.12,13 The study baseline wasset at 1984 for the NHS or the first follow-up
cycle since recruitment for the NHS II (1991) andthe HPFS (1988) for identifying participants whoreported quitting smoking.
In analyses of the risk of type 2 diabetes, participants with prevalent diabetes, cardiovasculardisease, or cancer at baseline were excluded; andin analyses of mortality, participants with prevalent cardiovascular disease and cancer at baseline
were excluded. The exclusion of prevalent chronic
diseases was critical for reducing the probability
624

n engl j med 379;7that participants had quit smoking owing toexisting diseases. For all analyses, we also excluded participants with missing information on
smoking status in two or more consecutive cycles
and those who completed the baseline questionnaire only. In diabetes analyses, participants witha missing date of diagnosis were also excluded.
After the exclusions, 162,807 participants were
included in the diabetes analyses and 170,723
were included in the mortality analyses.
This study was approved by the institutional
review board at Brigham and Women’s Hospitaland the Harvard T.H. Chan School of Public
Health. The return of a completed questionnaire
was considered to indicate informed consent.
The last author had full access to all the data inthe study and vouches for the completeness andaccuracy of the data and data analysis.
Assessment of Smoking Status and Weight
ChangeIn each 2-year survey cycle, we identified participants who had reported that they were smokers
in the previous cycle but were past smokers in
the current cycle, assuming the beginning of theprevious cycle as the onset of quitting. We calculated the duration of smoking cessation fromthe onset of quitting to the relapse of smoking,occurrence of study outcomes, or the end offollow-up (Table S1 in the Supplementary Appendix). Quitters were mutually exclusively definedas transient quitters (participants who reported
being past smokers in the current cycle but being current smokers in previous and next cycles),recent quitters (2 to 6 consecutive years sincesmoking cessation), and long-term quitters (>6consecutive years since smoking cessation). We
replaced missing information on smoking status
with assessments in the previous cycle only
(4.4% of participants for diabetes analyses and4.6% for mortality analyses). In these cohorts,
participant-reported smoking status and bodyweight have been shown to be highly accurate.14,15
Because the biennial weight-change trajectory
overlapped with that of persons who had neversmoked after 6 years of cessation (Text 2 in the
Supplementary Appendix), we focused on weightchange within the first 6 years after quitting,which was consistent with a previous study.16
Missing body-weight estimates were replaced withlast available values (9.7% of participants for diabetes analyses and 9.6% for mortality analyses).

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Smoking Cessation, Weight, Diabetes, and Mortality

We defined the “no weight gain” group as those
who gained no weight or lost weight, and thenwe applied cutoff points of 0.1 to 5.0 kg, 5.1 to
10.0 kg, and more than 10.0 kg to define othergroups.4 In a sensitivity analysis, we grouped participants according to quartiles of weight gain.
Assessment of Physical Activity and Diet

Physical activities were assessed with the use ofa validated questionnaire regarding time spent
on up to 10 recreational activities and were
quantified as metabolic equivalent tasks (METs)
in hours per week.17 In 1984, 1986, and every
4 years thereafter, a validated food-frequency
questionnaire was administered in the NHS toassess diet. Diet has been assessed every 4 years
in the NHS II and the HPFS with the use ofsimilar food-frequency questionnaires since 1991
and 1986, respectively. Overall diet quality wasassessed according to the Alternative Healthy
Eating Index (AHEI) score (range, 0 to 110, withhigher scores indicating a healthier diet).18
Assessment of Outcomes

Once participants reported a physician diagnosis
of diabetes in questionnaires that were completed
every 2 years, they were mailed a validated supplementary questionnaire19 to confirm the diagnosis (Text 3 in the Supplementary Appendix).
We identified deaths through searches of the
National Death Index, reports by the next of kin,or postal authorities.20 Deaths from cardiovascular disease were determined by study physicians’
review of medical records and death certificateswith diagnostic codes of the International Classification of Diseases, 9th Revision.
Statistical Analysis

Because of the same study design and relatively
homogenous populations in the cohorts, datafrom the three cohorts were pooled to maximize
statistical power. Person-time for each participant
was counted from the return of the baseline
questionnaire to the occurrence of study outcomes, last return of a valid follow-up questionnaire, or the end of follow-up (June 2012 for the
NHS, January 2012 for the HPFS, and June 2013
for the NHS II), whichever happened first. For the
diabetes analyses, follow-up was further censoredon the incidence of cancer or cardiovascular disease, including myocardial infarction, stroke, andcoronary-artery bypass surgery, because thesen engl j med 379;7

conditions are likely to lead to changes in bothsmoking status and body weight.
We used proportional-hazards regression to
examine the association of smoking cessation
with the incidence of type 2 diabetes, death fromcardiovascular disease, and death from any cause.
We used missing indicators for missing values ofcategorical variables, including physical activity,
AHEI score, and intakes of total energy and alcohol (missing in 3.0 to 17.4% of participants). Ina sensitivity analysis, we used a multiple-imputation procedure to impute values for missing dataon these variables before making categories(Text 4 in the Supplementary Appendix). Participants with missing data on multivitamin use(15.2% of participants) were assumed to be nonusers. To minimize reverse-causation bias by the“ill quitter effect” in the mortality analyses, we
stopped updating smoking status on the development of cancer, nonfatal vascular diseases,
chronic obstructive pulmonary disease, or type 2
diabetes. We did not find evidence suggesting
potential violation of the proportional-hazards
assumption for any exposure–outcome associations (Text 5 in the Supplementary Appendix).
A cubic spline regression model was fitted todelineate the association with duration of smoking cessation. Interactions with weight change
were tested by a likelihood-ratio test comparing
models with and without product terms between
duration-of-smoking-cessation spline variables andweight change. The estimated coefficients fromthe cubic spline regression were used to project
the associations in three-dimensional figures(R rgl package).21 In secondary analyses among
quitters, we modeled the association of dietquality and physical-activity changes after quitting in relation to weight changes using a multivariable-adjusted, mixed-effects model (Text 6 in
the Supplementary Appendix). In addition, by
including persons who reported quitting since1978 in the NHS, we modeled the long-term
trajectory of the risk of type 2 diabetes among
quitters who maintained cessation for up to 30
years. Lastly, to assess potential mediation effects of weight change, data were divided into
6-year intervals, and hazard ratios were compared in models with and without adjustment
for weight change (Text 7 in the Supplementary
Appendix).22
All P values presented were two-sided, withstatistical significance determined by a false

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625

T h e n e w e ng l a n d j o u r na l o f m e dic i n e

discovery rate of less than 0.05 (Text 8 in the
Supplementary Appendix).23 Data were analyzed
with the use of SAS software, version 9.4 (SASInstitute), and R software, version 3.3.2 (R Foundation).

R e sult s
Characteristics of the Study Participants

The proportion of past smokers steadily increased
in all cohorts during follow-up (Fig. S1 in the
Supplementary Appendix). Table 1 presents participants’ characteristics according to personyears by smoking status for diabetes analyses.
Participants’ characteristics for mortality analyses are presented in Table S2 in the Supplementary Appendix.
Smoking Cessation, Weight Change,
and Incidence of Type 2 Diabetes

During a mean of 19.6 years of follow-up, 12,384
cases of type 2 diabetes were identified and confirmed. Overall, recent quitters had a higher riskof type 2 diabetes than current smokers (Table 2).
In cubic spline analyses, the risk of type 2 diabetes peaked at 5 to 7 years since quitting andgradually decreased thereafter (Fig. 1A). Whenthe analysis was restricted to the NHS participants with the longest follow-up duration since1978, the risk of type 2 diabetes dropped to thatamong participants who had never smoked after
30 years of cessation (Fig. S2 in the Supplementary Appendix).
Weight gain modified the association between
smoking cessation and risk of type 2 diabetes(P<0.001 for interaction). The hazard ratios ascompared with current smokers were 1.08 (95%
confidence interval [CI], 0.93 to 1.26) among
recent quitters without weight gain, 1.15 (95%CI, 0.99 to 1.33) among those with weight gainof 0.1 to 5.0 kg, 1.36 (95% CI, 1.16 to 1.58)
among those with weight gain of 5.1 to 10.0 kg,
and 1.59 (95% CI, 1.36 to 1.85) among thosewith weight gain of more than 10.0 kg. The riskof type 2 diabetes among recent quitters without
weight gain more quickly approached the risk
among persons who had never smoked than did
the risk among quitters who gained weight(Fig. 1B). In the three-dimensional illustration of
the trajectory of the risk of type 2 diabetes according to years since smoking cessation and weightchange (Fig. S3A in the Supplementary Appen626

n engl j med 379;7dix), the peak of risk was observed among quitters with the most weight gain at 5 to 7 yearsof cessation. In the mediation analysis, weightchange within 6 years after cessation explained
68.4% (95% CI, 8.3 to 98.1) of the elevated riskof type 2 diabetes among those who reported
quitting smoking.
Smoking Cessation, Weight Change,
and Mortality

For the mortality analyses, we documented a
total of 23,867 deaths, of which 5492 were due
to cardiovascular disease. As compared withcurrent smokers, hazard ratios for death fromcardiovascular disease were 0.69 (95% CI, 0.54
to 0.88) among recent quitters without weight
gain, 0.47 (95% CI, 0.35 to 0.63) among thosewith weight gain of 0.1 to 5.0 kg, 0.25 (95% CI,
0.15 to 0.42) among those with weight gain of
5.1 to 10.0 kg, 0.33 (95% CI, 0.18 to 0.60) among
those with weight gain of more than 10.0 kg,
and 0.50 (95% CI, 0.46 to 0.55) among longerterm quitters (Table 2). The corresponding hazard ratios for death from any cause were 0.81
(95% CI, 0.73 to 0.90), 0.52 (95% CI, 0.46 to0.59), 0.46 (95% CI, 0.38 to 0.55), 0.50 (95% CI,
0.40 to 0.63), and 0.57 (95% CI, 0.54 to 0.59).
Cubic spline analyses showed that cardiovascular mortality decreased substantially after quitting, reached a nadir at 10 to 15 years, and thenrose slowly but never reached the level of current
smokers (Fig. 2A). In stratified analyses, such apattern of associations was observed in all weightgain groups, but among those without weight
gain, cardiovascular mortality decreased after
quitting for 5 to 10 years and plateaued thereafter without the upward trend (Fig. 2B). In thethree-dimensional illustration, we found that ina small group of quitters (0.13% of total personyears) with weight gain of at least 18.0 kg at
6 years since smoking cessation, the cardiovascular mortality gradually approached the levelof current smokers during an extended period of
follow-up (Fig. S3B in the Supplementary Appendix).
All-cause mortality showed a monotonic reduction at 5 to 7 years of cessation and plateaued
afterward (Fig. 2C). This pattern was observed in
all weight-change groups, except that quitterswithout weight gain had a linear risk reduction
after quitting (Fig. 2D). The three-dimensional
illustration of all-cause mortality corroborated

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395,87253.3±10.4
24.1±4.3

Person-yr†

Age (yr)

Baseline body-mass index‡

n engl j med 379;7

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28.2

Family history of diabetes (%)

8.4

12.7

0.8–10.71747±547

0.6–11.01756±5643.550.9±9.9

4.0–28.8

3.047.6±9.7

2.7–21.5

42.1

27.1

29.5

31.1

24.8

0.9

1.0

1.1

97.0

24.6±4.756.1±11.3

37,444≤0 kg

1761±551

0.9–11.1

3.950.5±9.9

4.4–28.3

12.8

43.0

26.7

29.2

30.4

21.2

0.9

0.9

0.9

97.3

23.4±3.854.5±11.0

52,147

0.1–5.0 kg

1767±548

0.6–9.42.949.3±9.6

3.4–23.5

10.2

41.6

30.0

30.6

34.9

24.4

0.9

0.8

0.8

97.5

24.4±4.2

54.2±10.6

29,767

5.1–10.0 kg

1783±571

0.4–6.8

2.0

48.8±9.4

2.7–19.6

8.1

41.1

32.1

31.8

37.6

30.4

0.8

0.7

0.9

97.6

26.4±5.552.2±10.5

19,424>10.0 kg

Recent Quitters According to Weight Gain within 6 Years
after Quitting

1780±535

0.9–10.1

3.6

52.0±9.6

4.3–29.6

13.6

50.0

28.2

30.6

39.9

28.3

0.8

0.9

0.9

97.4

24.3±4.662.3±10.5

185,838

Long-Term
Quitters

1764±561

0.9–10.23.549.3±9.7

3.5–25.2

10.6

42.9

28.2

31.5

30.4

21.6

0.9

0.8

0.9

97.4

24.2±4.451.5±10.9

12,853

Transient
Quitters

1814±561

0–4.3

1.1

50.8±10.2

4.8–29.3

13.5

46.7

28.9

31.7

32.3

23.8

1.3

1.5

1.4

95.8

24.5±4.652.5±11.9

2,451,805

Never
Smoked*	Plus–minus values are means ±SD. All values are standardized to the age distribution of the study population. Recent quitters were defined as participants who had stopped smoking
for 2 to 6 consecutive years. Long-term quitters were defined as participants who had stopped smoking for more than 6 consecutive years. Transient quitters were defined as participants who reported being past smokers in the current 2-year survey cycle but being current smokers in the previous and next cycles. MET denotes metabolic equivalent tasks.
†	Person-years are based on the analyses for type 2 diabetes.
‡	The body-mass index is the weight in kilograms divided by the square of the height in meters.
§	Race was reported by the participants. Percentages may not total 100 because of rounding.
¶	Scores on the Alternative Healthy Eating Index range from 0 to 110, with higher scores indicating a healthier diet.

Total energy intake (kcal/day)Interquartile range

MedianAlcohol consumption (g/day)

Alternative Healthy Eating Index score¶

Interquartile range

MedianPhysical activity (MET-hr/wk)

37.8

30.1

Family history of myocardial infarction (%)

Multivitamin use (%)

28.2

0.8

Other
20.5

0.8

Asian

Participant-reported hypercholesterolemia (%)

0.8

Black

Participant-reported hypertension (%)

97.6

White

Race (%)§

Current
Smokers

Characteristic

Table 1. Age-Standardized Characteristics of Participants in the Nurses’ Health Study, the Nurses’ Health Study II, and the Health Professionals Follow-up Study.*

Smoking Cessation, Weight, Diabetes, and Mortality

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627

T h e n e w e ng l a n d j o u r na l o f m e dic i n eTable 2. Pooled Hazard Ratios for Association between Smoking Cessation and the Incidence of Type 2 Diabetes, Death from Cardiovascular
Disease, and Death from Any Cause.*
VariableCases/Person-yr

Hazard Ratio (95% CI)
Adjusted for
Age

Adjusted forBaseline BMI

Adjusted forMultiple Variables

Type 2 diabetes
Current smokers

1,547/395,872

1.00 (reference)  1.00 (reference)

1.00 (reference)

Recent quitters†

836/148,082

1.35 (1.24–1.47)‡

1.25 (1.14–1.36)‡

1.22 (1.12–1.32)‡

No weight gain

204/37,444

1.27 (1.10–1.48)‡

1.09 (0.94–1.27)

1.08 (0.93–1.26)

Weight gain of 0.1–5.0 kg

206/52,147

0.96 (0.83–1.11)

1.14 (0.99–1.32)

1.15 (0.99–1.33)

Weight gain of 5.1–10.0 kg

188/29,767

1.52 (1.30–1.77)‡

1.44 (1.23–1.68)‡

1.36 (1.16–1.58)‡

Weight gain of >10.0 kg

196/19,424

2.58 (2.22–2.99)‡

1.66 (1.43–1.94)‡

1.59 (1.36–1.85)‡

Long-term quitters

1,168/185,838

1.15 (1.07–1.25)‡

1.03 (0.96–1.12)

1.02 (0.94–1.10)

Transient quitters

54/12,853

1.12 (0.85–1.47)

1.09 (0.83–1.44)

1.09 (0.83–1.44)

Never smoked

8,779/2,451,805

0.91 (0.86–0.96)‡

0.77 (0.72–0.81)‡

0.72 (0.68–0.76)‡

Death from cardiovascular disease§
Current smokers

1,488/524,182

1.00 (reference)  1.00 (reference)

1.00 (reference)

Recent quitters†

167/154,259

0.44 (0.37–0.51)‡

0.44 (0.37–0.51)‡

0.48 (0.41–0.56)‡

No weight gain

68/39,637

0.63 (0.49–0.80)‡

0.63 (0.49–0.80)‡

0.69 (0.54–0.88)‡

Weight gain of 0.1–5.0 kg

46/53,969

0.39 (0.29–0.52)‡

0.41 (0.31–0.55)‡

0.47 (0.35–0.63)‡

Weight gain of 5.1–10.0 kg

14/30,926

0.23 (0.14–0.39)‡

0.23 (0.14–0.40)‡

0.25 (0.15–0.42)‡

Weight gain of >10.0 kg
Long-term quitters
Never smoked

11/20,670

0.36 (0.20–0.65)‡

0.32 (0.18–0.59)‡

0.33 (0.18–0.60)‡

656/256,194

0.46 (0.42–0.51)‡

0.46 (0.42–0.50)‡

0.50 (0.46–0.55)‡

3,181/3,003,966

0.34 (0.32–0.36)‡

0.31 (0.29–0.33)‡

0.34 (0.32–0.37)‡

Death from any cause§
Current smokers

6,537/519,569

1.00 (reference)  1.00 (reference)

1.00 (reference)

Recent quitters†

880/153,642

0.53 (0.49–0.57)‡

0.53 (0.49–0.57)‡

0.58 (0.54–0.62)‡

No weight gain

360/39,386

0.75 (0.67–0.83)‡

0.74 (0.67–0.83)‡

0.81 (0.73–0.90)‡

Weight gain of 0.1–5.0 kg

236/53,815

0.44 (0.39–0.51)‡

0.46 (0.40–0.52)‡

0.52 (0.46–0.59)‡

Weight gain of 5.1–10.0 kg

115/30,826

0.42 (0.35–0.50)‡

0.42 (0.35–0.51)‡

0.46 (0.38–0.55)‡

76/20,616

0.51 (0.40–0.64)‡

0.48 (0.38–0.61)‡

0.50 (0.40–0.63)‡

Long-term quitters

Weight gain of >10.0 kg

3,252/253,822

0.50 (0.48–0.53)‡

0.50 (0.48–0.52)‡

0.57 (0.54–0.59)‡

Never smoked

13,198/2,994,849

0.32 (0.31–0.33)‡

0.31 (0.30–0.32)‡

0.35 (0.34–0.37)‡*	Hazard ratios and 95% confidence intervals (CIs) were estimated with the use of a Cox proportional-hazards model. Multivariate analyses
were adjusted for age (in months, continuous), cohort (Nurses’ Health Study, Nurses’ Health Study II, or Health Professionals Follow-up
Study), sex (male or female), race (white, black, Asian, or other), physical activity (in quintiles), baseline body-mass index (BMI, in continuousand quadratic terms), alcohol intake (0, <5.0, 5.0 to 9.9, 10.0 to 14.9, 15.0 to 29.9, or ≥30.0 g per day), hypertension (yes or no), hypercholesterolemia (yes or no), family history of diabetes (yes or no), multivitamin use (yes or no), Alternative Healthy Eating Index score (in quintiles),and total energy intake (in quintiles). Hazard ratios for death from cardiovascular disease and death from any cause were also adjusted forfamily history of myocardial infarction (yes or no).
†	In analyses involving recent quitters with stratification according to weight change since quitting, 0.3% of the cases (42 cases) and 0.3% of
the person-time in the analysis of type 2 diabetes, 0.1% of the cases (28 cases) and 0.2% of the person-time in the analysis of death fromcardiovascular disease, and 0.4% of the cases (93 cases) and 0.3% of the person-time in the analysis of death from any cause with missing
data regarding weight change were removed from the stratified analyses, and therefore the total number of cases and total person-time acrossweight-change categories were smaller than those in the analyses involving total recent quitters, without consideration of subsequent weightchange.
‡	The false discovery rate was less than 0.05.
§	There were no cases among transient quitters for the analyses of death from cardiovascular disease and death from any cause.

628

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Smoking Cessation, Weight, Diabetes, and Mortality

A
All quitters

Hazard Ratio for Type 2 Diabetes

1.0

0.8

0.6

0

5

10

15

20

25

30

Years since Smoking Cessation

B
Weight Gain after Quitting≤0 kg
0.1–5.0 kg

5.1–10.0 kg>10.0 kg

Current smokers
Never smoked

2.0

Secondary and Sensitivity Analysesn engl j med 379;7

1.2

0.4

findings in the stratified analyses (Fig. S3C in
the Supplementary Appendix).
Among quitters, each increase of 10 MET-hours
per week in physical activities was associatedwith 0.13 kg (95% CI, 0.11 to 0.15) less weight
gain, and each 10-point increase in the AHEI
score was associated with 0.26 kg (95% CI, 0.21
to 0.32) less weight gain. (For details, see Table
S3 in the Supplementary Appendix.)
Results were similar when we did not carryforward valid smoking status to replace missing
values (Table S4 in the Supplementary Appendix), when the start of cessation was defined as
the beginning of the cycle that participants firstreported being past smokers (Table S5 in the
Supplementary Appendix), when recent quitterswere defined as quitting for 2 to 8 consecutive
years rather than 2 to 6 years (Table S6 in the
Supplementary Appendix), when the model used
quartiles of weight change after cessation (Table
S7 in the Supplementary Appendix), or when weused imputed values for missing covariates in
the analyses (Table S8 in the Supplementary Appendix).

Never smoked

Current smokers

1.4

Hazard Ratio for Type 2 Diabetes

Figure 1. Association between Duration of Smoking
Cessation and Risk of Type 2 Diabetes.
Panel A shows the risk of type 2 diabetes according toyears since smoking cessation, as compared with therisk among current smokers. P<0.001 for nonlinearity.
“All quitters” indicates all persons who had reported
quitting smoking. Panel B shows the risk of type 2 diabetes according to years since smoking cessation andweight change within 6 years after quitting, as comparedwith the risk among current smokers. P values for nonlinearity were 0.33 for no weight gain, 0.59 for weightgain of 0.1 to 5.0 kg, 0.01 for weight gain of 5.1 to 10.0 kg,
and less than 0.001 for weight gain of more than 10.0 kg.
Multivariate analyses were adjusted for age (in months,
continuous), cohort (Nurses’ Health Study [NHS],
Nurses’ Health Study II [NHS II], or Health Professionals Follow-up Study [HPFS]), sex (male or female), race
(white, black, Asian, or other), physical activity (in quintiles), baseline body-mass index (BMI, in continuousand quadratic terms), alcohol intake (0, <5.0, 5.0 to 9.9,
10.0 to 14.9, 15.0 to 29.9, or ≥30.0 g per day), historyof hypertension (yes or no), history of hypercholesterolemia (yes or no), family history of diabetes (yes or no),multivitamin use (yes or no), Alternative Healthy Eating Index score (in quintiles), and total energy intake(in quintiles). Dotted lines represent 95% confidence
intervals.

1.5

1.0

0.5
0

5

10

15

20

25

30

Years since Smoking Cessation

Discussion
In three cohorts of U.S. men and women, we
observed a temporary elevation in the risk oftype 2 diabetes after smoking cessation, primarily among quitters who gained weight. However,both cardiovascular and all-cause mortality decreased on smoking cessation, and the reduction
was largely sustained during extended durationof smoking cessation, even among those who
gained weight.
Our observation of the short-term elevation in
the risk of type 2 diabetes after smoking cessa-

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629

T h e n e w e ng l a n d j o u r na l o f m e dic i n e

All quitters

Current smokers

Weight Gain after Quitting:

Never smoked

5.1–10.0 kg>10.0 kg

Hazard Ratio for Death from CVD

B
Hazard Ratio for Death from CVD

A

≤0 kg
0.1–5.0 kg

1.0
0.8
0.6
0.4
0.2

0

5

10

15

20

25

30

1.0
0.8
0.6
0.4
0.2

0

5

Years since Smoking Cessation

C

15

20

25

30

25

30

D
1.0

Hazard Ratio for Deathfrom Any Cause

1.0

Hazard Ratio for Deathfrom Any Cause

10

Years since Smoking Cessation

0.8
0.6
0.4
0.2

0

5

10

15

20

25

0.8
0.6
0.4
0.2

30

0

Years since Smoking Cessation

5

10

15

20

Years since Smoking Cessation

Figure 2. Association between Duration of Smoking Cessation and Risk of Death from Cardiovascular Disease (CVD) and Deathfrom Any Cause.
Panel A shows the risk of death from CVD according to years since smoking cessation, as compared with the risk among current smokers.
P<0.001 for nonlinearity. Panel B shows the risk of death from CVD according to years since smoking cessation and weight change within
6 years after quitting, as compared with the risk among current smokers. P values for nonlinearity were 0.01 for no weight gain and lessthan 0.001 for weight gain of 0.1 to 5.0 kg, 5.1 to 10.0 kg, and more than 10.0 kg. Panel C shows the risk of death from any cause according to years since smoking cessation, as compared with the risk among current smokers. P<0.001 for nonlinearity. Panel D shows therisk of death from any cause according to years since smoking cessation and weight change within 6 years after quitting, as comparedwith the risk among current smokers. P values for nonlinearity were 0.95 for no weight gain and less than 0.001 for weight gain of 0.1 to
5.0 kg, 5.1 to 10.0 kg, and more than 10.0 kg. Multivariate analyses were adjusted for age (in months, continuous), cohort (NHS, NHS II,
or HPFS), sex (male or female), race (white, black, Asian, or other), physical activity (in quintiles), baseline BMI (in continuous and quadratic terms), alcohol intake (0, <5.0, 5.0 to 9.9, 10.0 to 14.9, 15.0 to 29.9, or ≥30.0 g per day), history of hypertension (yes or no), historyof hypercholesterolemia (yes or no), family history of diabetes (yes or no), family history of myocardial infarction (yes or no), multivitamin use (yes or no), Alternative Healthy Eating Index score (in quintiles), and total energy intake (in quintiles). Dotted lines represent
95% confidence intervals.

tion was consistent with previous studies, whichshowed that former smokers who had quit recently had a significantly higher risk of type 2
diabetes than persons who had never smoked,
although those who had sustained smoking cessation over a longer period did not.5,6,24-27 Although the weight gain that is commonly observed after smoking cessation may explain such
an elevated risk of diabetes, findings from previous studies did not support such a hypothesis,5,6630

n engl j med 379;7

probably owing to the lack of long-term, repeated assessments of subsequent changes insmoking status and body weight. Indeed, because quitters are likely to have a relapse,11 theirsubsequent disease risk may vary according to
the duration of cessation and concurrent weightchange. In our analyses, we estimated thatweight change within 6 years after quitting explained 68.4% of the increased risk of type 2
diabetes.

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Smoking Cessation, Weight, Diabetes, and Mortality

As compared with a short-term increase in therisk of type 2 diabetes, cardiovascular mortality
decreased substantially on cessation in all weightchange groups. It is known that most excessive
cardiovascular risk is eliminated within the firstfew years of cessation.28,29 Two investigations
explicitly examined the associations of smoking
cessation with cardiovascular disease risk according to weight change, but results were mixed,
probably because of small numbers of cases
among quitters in these cohorts.7,8 In a Koreancohort of men, a lower risk of cardiovasculardisease was observed among those who reported
quitting smoking and had either stable or increased body weight but not among those wholost weight.9 In addition to small sample sizes,
the discrepant findings in these studies can also
potentially be ascribed to the important methodologic issue of the “ill quitter effect” — that is,smokers with preexisting diseases are more likely
to quit but have a much higher risk of premature
death,30 which was not explicitly addressed inthese studies.
Our findings of a substantial reduction in allcause mortality on cessation were consistent withprevious studies.1,31 We also found that the reduction in total mortality reached a nadir after 10 to
15 years of quitting and plateaued afterward.
Further analyses showed that such an L-shape
relationship was largely driven by quitters withweight gain; among quitters without weight gain,
the mortality reduction was quite linear over time.
Overall, our data showed that subsequent
weight gain, on average, did not attenuate theapparent benefits of smoking cessation on reducing cardiovascular mortality or extending longevity. However, preventing excessive weight gain
may maximize the health benefits of smoking
cessation through reducing the short-term riskof diabetes and further lowering the long-termrisk of death.
Our analyses provided further evidence suggesting that improving diet quality and increasing
physical activities may help quitters to achieve
their weight-maintenance goals. Several long-term(≥1 year) smoking-cessation trials and observational studies have shown the beneficial effects
of increasing physical activities on mitigating
weight gain after quitting.32-34 Exercise might also
improve short-term smoking abstinence.35 Healthy
dietary patterns (e.g., a diet with a high AHEI
score, the Mediterranean diet, and the Dietaryn engl j med 379;7

Approaches to Stop Hypertension diet), which
typically consist of foods that increase satiety,such as whole fruits, vegetables, and wholegrains,36 may attenuate the increased appetite
after smoking cessation. It has been shown thatsmokers with higher consumption of fruits andvegetables gained less weight after quitting thanthose with low consumption,37 although further
studies, especially clinical trials, are needed tofurther elucidate the role of diet quality in weight
management among quitters. Meanwhile, evidence from the PREDIMED (Prevención con Dieta
Mediterránea) study suggested that improved dietquality could convey similar health benefits on
reducing cardiovascular disease risk among persons who have ever smoked and those who neversmoked.38 Taken together, although lifestylemodification after smoking cessation could bechallenging to some quitters, existing evidence
suggests that lifestyle changes, in particular increasing physical activities,32 are an effective
strategy for weight management among quittersand do not appear to increase the possibility of
relapse among quitters.
Because the exact date of smoking cessation
was not ascertained, the assessments of durationof smoking cessation and related weight-change
estimates were subject to misclassifications. However, given the prospective study design, suchmeasurement errors were unrelated to the ascertainment of outcomes and thus were more likely
to bias the true associations toward the null. In
addition, if quitters who had a relapse reported
continued cessation or if quitters underreported
their weight gain owing to social-desirability bias,
true associations would have been likely to be attenuated toward the null because these persons
still had an elevated disease risk. Carrying forward the last available values to replace missing
data on smoking status and body weight may
have introduced misclassifications. However, theproportions of missing values for smoking status and weight were low, and we observed similar associations in analyses restricted to participants without missing values for these variables,
which suggests that any effect of misclassification was likely to be small. Lastly, because ourparticipants were mostly white health professionals without major chronic diseases at baseline, the generalizability of our findings to othergroups may be limited.
In conclusion, our findings suggest that anejm.org

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631

Smoking Cessation, Weight, Diabetes, and Mortality

temporary increase in the risk of type 2 diabetes
due to weight gain after smoking cessation did
not attenuate the benefits of smoking cessation
on reducing total and cardiovascular mortality.
Supported by research grants (CA186107, CA176726, CA167552,
HL034594, HL035464, and DK112940) from the National InstiReferences
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